Abstract

Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). ATL cells possess a CD4+ CD25+ phenotype, similar to that of regulatory T cells (Tregs). Tax has been reported to play a crucial role in the leukemogenesis of HTLV-1. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the viral genomic RNA, is expressed in all ATL cases and induces neoplastic and inflammatory disease in vivo. To test whether HBZ and Tax are both required for T cell malignancy, we generated HBZ/Tax double transgenic mice in which HBZ and Tax are expressed exclusively in CD4+ T cells. Survival was much reduced in HBZ/Tax double-transgenic mice compared with wild type littermates. Transgenic expression of HBZ and Tax induced skin lesions and T-cell lymphoma in mice, resembling diseases observed in HTLV-1 infected individuals. However, Tax single transgenic mice did not develop major health problems. In addition, memory CD4+ T cells and Foxp3+ Treg cells counts were increased in HBZ/Tax double transgenic mice, and their proliferation was enhanced. There was very little difference between HBZ single and HBZ/Tax double transgenic mice. Taken together, these results show that HBZ, in addition to Tax, plays a critical role in T-cell lymphoma arising from HTLV-1 infection.

Keywords

HTLV-1 HBZ Tax Transgenic mice Lymphoma

Electronic supplementary material

The online version of this article (doi:10.1007/s00705-014-2099-y) contains supplementary material, which is available to authorized users.

Notes

Acknowledgments

This work was supported by a grant from National Natural Science Foundation of China to TZ (No.31200128); a Grant-in-aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan to MM. The authors thank Aaron Coutts for proofreading the manuscript.

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

Supplemental Fig. 1 Tax could not induce Foxp3 expression. ATL-43T cells, an ATL cell line, were transduced with lentiviral vector encoding Tax, or with empty vector. One and two days after infection, cells were stained with anti-Foxp3 in addition to anti-NGFR and then analyzed by flow cytometry. (PPTX 76 kb)